Sustained release drug delivery systems comprising a water soluble therapeutic agent and a release modifier

ABSTRACT

A biocompatible, sustained release intraocular drug delivery system comprising a protein or polynucleotide therapeutic agent, a polymeric carrier for the therapeutic agent and a long chain fatty alcohol release modifier. The biocompatible, sustained release intraocular drug delivery system can be used to treat an ocular condition.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.11/556,503, filed Nov. 3, 2006, and hereby incorporated by reference.

BACKGROUND

The present invention relates to sustained release drug delivery systemsand methods for therapeutic use of the sustained release drug deliverysystems. In particular, the present invention relates to sustainedrelease drug delivery systems containing a water soluble therapeuticagent and a release modifier to modify the rate of release of thetherapeutic agent from the drug delivery system, and methods for makingand using such drug delivery systems. The drug delivery systemsdisclosed herein can be used for example in methods for treating anocular condition of a patient.

Various therapeutic agents (such as proteins and polynucleotides) havebeen used to treat an ocular condition. A difficulty with administrationof a therapeutic agent to treat an ocular condition includes being ableto appropriately deliver the therapeutic agent in proximity to thedesired target tissue. For the treatment of a retinal condition such asmacular edema or macular degeneration the target tissue can be theretina or the macula. For the treatment of glaucoma the target tissuecan be the cilliary body or photoreceptors of the retina. When atherapeutic agent is not delivered in proximity to the target tissue,for example when a topical pharmaceutical (i.e. an eye drop) isadministered to the cornea of eye in order to treat a target tissuewithin the anterior chamber or the posterior chamber, the therapeuticagent can arrive at the target site in a sub-therapeutic amount and withundesirable side effects upon other tissues. Side effects can includeundesirable systemic effects which can result when a relatively largeamount of the therapeutic agent is administered, so that a therapeuticamount of the therapeutic agent can be present after administration atthe target tissue site. Ocular side effects, such as cataract formationand elevated intraocular pressure, can also result when the therapeuticagent is not administered at a location proximate to the target tissuesite.

Another difficulty with administration of a therapeutic agent to treatan ocular condition can result from the desirability of maintaining atherapeutically effective amount of the therapeutic agent proximate tothe target tissue for a prolonged period of time, such as for severalweeks or months. Thus, because topical formulations of therapeuticagents or aqueous injectables thereof typically disperse, diffuse or aredegraded to subtherapeutic levels of the therapeutic agent in a matterof minutes or hours, frequent re-dosing is therefore required to treat achronic ocular condition.

Sustained release drug delivery systems are known. For example U.S. Pat.No. 6,713,081 discloses polyvinyl alcohol intraocular implants. See alsoU.S. Pat. Nos. 4,521,210; 4,853,224; 4,997,652; 5,164,188; 5,443,505;5,501,856; 5,766,242; 5,824,072; 5,869,079; 6,074,661; 6,331,313;6,369,116; and 6,699,493 and U.S. patent publication 20040170665.

Additionally, release of protein or polynucleotide therapeutic agentfrom a sustained release drug delivery system is known. See e.g. JacksonJ. et al., The encapsulation of ribozymes in biodegradable polymericmatrices, Int J of Pharmaceutics 243 (2002) 43-55, discusses sustainedrelease formulations of ribozymes comprising injectable PLA and PLGAmicrospheres or a polycaprolactone paste. Jackson suggests controllingthe release rate by altering the ribozyme loading. Rosa G., et al., Anew delivery system for antisense therapy: PLGA microspheresencapsulating olignucleotide/polyethyleneimine solid complexes, Int J ofPharmaceutics 254 (2003) 89-93, discloses antisense oligonucleotide PLGAmicrospheres wherein the in vitro release profile can be changed bychanging the nitrogen/phosphate ratio of a polyethylenimine used, drugload or the type of PLGA used. Carrasquillo K. et al., Controlleddelivery of the anti-VEGF aptamer EYE001 withpoly(lactic-co-glycolic)acid microspheres, IOVS January 2003 44(1),discusses anti-VEGF PLGA microspheres. Khan A. et al., Sustainedpolymeric delivery of gene silencing antisense ODNs, siRNA, DNAzymes andribozymes: in vitro and in vivo studies, discusses PLGA microspheres ofsiRNAs, oligonucleotides, ribozymes and DNAzymes, including one or moreof these molecules with an attached lipophilic group to change therelease rate. Additionally, see also U.S. patent application Ser. Nos.11/116,698; 11/364,687, and 11/370,301.

A problem with known sustained release drug delivery systems includesburst release of the therapeutic agent from the drug delivery system. Aburst release occurs when more than about 30% of the therapeutic agentcontained by the drug delivery system is released from the drug deliverysystem within about 48 hours after in vivo or in vitro placement (byinjection or implantation) of the drug delivery system. Burst releasecan be a particular problem with water soluble drugs which have apropensity to quickly enter solution in an aqueous physiologicalenvironment. A water-soluble therapeutic agent (a therapeutic agent canbe referred to synonymously as a drug) is defined as a drug of which 10mg or more can enter solution in one ml of water at room temperature (20degrees C.). A slightly or sparingly soluble drug has the property thatonly from 1 mg to 10 mg of the drug can form a solution in one ml ofwater at room temperature. A poorly soluble drug has the property thatonly less than 1 mg of the drug can form a solution in one ml of waterat room temperature. Water soluble drugs can include proteins andpolynucleotides. Sirna-027, is a highly water-soluble duplex siRNA thatcan form aqueous solutions of up to 500 mg/mL. A protein can be definedas a polypeptide which comprises two or more amino acid resides and apolynucleotide can be defined as a compound which comprises two or morenucleotides.

It is known to use a release modifier in a drug delivery system so as tomodify the rate at which a therapeutic agent is released from the drugdelivery system. See eg U.S. Pat. No. 7,048,946.

Aliphatic Alcohols

Aliphatic alcohols (also known synonymously as fatty alcohols or as longchain alcohols or as long chain fatty alcohols) are predominatelystraight chain organic molecules with an even number of carbon atomsderived from natural fats and oils. Aliphatic alcohols can be convertedto or derived from fatty acids and fatty aldehydes. It is known to usethe smaller aliphatic alcohols as additives in cosmetics and food, andas industrial solvents. Some larger aliphatic alcohols have been used asbiofuels.

Due to their amphipathic nature, aliphatic alcohols can behave asnonionic surfactants and find use as emulsifiers, emollients andthickeners in the cosmetics and food industries. Additionally, aliphaticalcohols are a common component of waxes, mostly as esters with fattyacids but also as alcohols themselves.

Natural Fatty alcohols can be derived from natural fats and oils and arehigh molecular straight chain primary alcohols. They include lauryl(C12), myrlstyl (C14), Cetyl (or palmityl: C16), stearyl (C18), Oleyl(C18, unsaturated), and Linoleyl (C18, polyunsaturated) alcohols.Synthetic fatty alcohols equivalent physically and chemically to naturalalcohols can be obtained from oleochemical sources such as coconut andpalm kernel oil. Fatty alcohols have been used as emulsifiers andemollients in skin creams, as well a as chemical intermediates. Animportant use of fatty alcohols is as raw material for the production offatty sulfate salts and alcohol ethoxylates for foaming and cleaningpurposes in the detergent industry. Chemical reactions of primaryalcohols include esterifications, ethoxylation, sulfation, oxidation andmany other reactions. Derivatives of fatty alcohols and their end useapplications include nonionic surfactants (ethoxylates andpropoxylates); anionic surfactants (alkyl sulfates and alkyl ethoxysulfates); chemical intermediates and polymerization modifiers (alkylhalides, alkyl mercaptans); quaternary ammonium compounds for detergentsanitisers, softners for textiles, phase transfer catalyst and biocides;antioxidants for plastics (alkyl thiopropionates and alkyl phosphites);lubricant additives (metallic and thio alkylphosphates); flavor andfragrance (aldehydes and ketones); PVC plasticizers (dialkyl Phthalates,adipates and trimellitates); coatings and inks (acrylate andmethacrylate esters), and; water treatment (acrylate and methacrylateesters) Large amount of fatty alcohols are used as special solvents,fillers in plasticizer and insulating materials for the buildingindustry. Fatty alcohols are used as ingredients in the industries ofagricultural, foodstuff, metal processing, cosmetics, lube additive,pharmaceutical, rubber, textile, perfume and flavoring as well assynthetic detergent.

Aliphatic alcohols include:

capryl alcohol (1-octanol)—8 carbon atomspelargonic alcohol (1-nonanol)—9 carbon atomscapric alcohol (1-decanol, decyl alcohol)—10 carbon atomslauryl alcohol (1-dodecanol)—12 carbon atomsmyristyl alcohol (1-tetradecanol)—14 carbon atomscetyl alcohol (1-hexadecanol: C₁₈H₃₄O)—16 carbon atoms and has amolecular weight of 242.45palmitoleyl alcohol (cis-9-hexadecan-1-ol)—16 carbon atoms, unsaturated,CH₃(CH₂)₅CH═CH(CH₂)₈OHstearyl alcohol (1-octadecanol)—18 carbon atomsisostearyl alcohol (16-methylheptadecan-1-ol)—18 carbon atoms, branched,(CH₃)₂CH—(CH₂)₁₅OHelaidyl alcohol (9E-octadecen-1-ol)—18 carbon atoms, unsaturated,CH₃(CH₂)₇CH═CH(CH₂)₈OHoleyl alcohol (cis-9-octadecen-1-ol)—18 carbon atoms, unsaturatedlinoleyl alcohol (9Z, 12Z-octadecadien-1-ol)—18 carbon atoms,polyunsaturatedelaidolinoleyl alcohol (9E, 12E-octadecadien-1-ol)—18 carbon atoms,polyunsaturatedlinolenyl alcohol (9Z, 12Z, 15Z-octadecatrien-1-ol)—18 carbon atoms,polyunsaturatedelaidolinolenyl alcohol (9E, 12E, 15-E-octadecatrien-1-ol)—18 carbonatoms, polyunsaturatedricinoleyl alcohol (12-hydroxy-9-octadecen-1-ol)—18 carbon atoms,unsaturated, diol, CH₃(CH₂)₅CH(OH)CH₂CH═CH(CH₂)₈OHarachidyl alcohol (1-eicosanol)—20 carbon atomsbehenyl alcohol (1-docosanol)—22 carbon atomserucyl alcohol (cis-13-docosen-1-ol)—22 carbon atoms, unsaturated,CH₃(CH₂)₇CH═CH(CH₂)₁₂OHlignoceryl alcohol (1-tetracosanol)—24 carbon atomsceryl alcohol (1-hexacosanol)—26 carbon atomsmontanyl alcohol, cluytyl alcohol (1-octacosanol)—28 carbon atomsmyricyl alcohol, melissyl alcohol (1-triacontanol)—30 carbon atoms, and;geddyl alcohol (1-tetratriacontanol)—34 carbon atoms

Behenyl alcohol, lignoceryl alcohol, ceryl alcohol, 1-heptacosanol,montanyl alcohol, 1-nonacosanol, myricyl alcohol, 1-dotriacontanol, andgeddyl alcohol are together classified as policosanol, with montanylalcohol and myricyl alcohol being the most abundant.

1-eicosanol (arachidyl alcohol) has the formula CH₃(CH₂)₁₈CH₂OH and amolecular weight of 298.55. Synonyms are 1-Icosanol; Icosan-1-ol;Icosanol; arachidic alcohol; eicosyl alcohol; 1-prydroxyeicosane, and;eicosanol-(1). It is a white solid with a melting point of 64-66° C.

What is needed therefore is a sustained release drug delivery system fora water soluble therapeutic agent from which drug delivery system thetherapeutic agent can be released without a burst effect.

SUMMARY

The present invention meets this need and provides is a sustainedrelease drug delivery system for a water soluble therapeutic agent fromwhich drug delivery system the therapeutic agent can be released withouta burst effect.

Our invention comprises drug delivery systems for extended or sustaineddrug release into an eye of a therapeutic agent. The drug deliverysystem can be in the form of implants or microparticles which uponintraocular administration provide a therapeutic amount of thetherapeutic agent for an extended time period, such as for at leastabout one week and for a period of time of up to twelve months.

Our intraocular drug delivery systems comprise a therapeutic agent, apolymeric carrier and a release modifier.

Therapeutic Agents

Therapeutic agents within the scope of our invention are water solubletherapeutic agents, such as proteins and polynucleotides. The termpolynucleotide includes oligonucleotides. An oligonucleotide contains 25or fewer nucleotides. Protein therapeutic agents useful in our inventioninclude peptides, proteins, antibodies, and antibody fragments (such asa monovalent fraction antigen-binding papain fragment (Fab) or abivalent fraction antigen binding pepsin fragment [F′ ab₂]), VEGF,monoclonal antibodies (such as Humira [adalimumab) for rheumatoid andpsoriatic arthritis], antibody fragments (such as Lucentis [ranibizumab]and Imclone's IMC-1121 Fab for acute macular degeneration [“AMD”]),polyclonal antibodies, and hormones such as human growth hormone(somatotropin).

Oligonucleotide (ONT) therapeutic agents useful in our invention includeshort interfering ribonucleic acids (siRNAs) such as Sirna-027 (SirnaTherapeutics) and Cand5 (Acuity Pharmaceuticals), oligonucleotideaptamers (single stranded RNA or DNA that binds proteins) such asMacugen (pegaptanib sodium, Genzyme), and microRNA and shRNA (shorthairpin RNA). The oligonucleotide therapeutic agent can be a 23-mer (23bases in a specific sequence). The RNA bases are adenosine, guanosine,uridine, and cytidine. Sirna-027 is a duplex RNA, each chain being a21-mer (19 base pairs plus two unpaired overhangs).”

Preferred drug delivery systems comprise, for example, a polymeric solidinsertable drug delivery device. Preferably, such drug delivery systemsare biodegradable, and are capable of being injected or surgicallyplaced within the anterior or posterior segment of the mammalian eye.

In one embodiment, a sustained-release intraocular drug delivery systemcomprises a therapeutic agent, a polymeric carrier and a releasemodifier associated with the therapeutic agent to permit the therapeuticagent to be released into the interior of an eye of an individual for atleast about one week after the drug delivery system is placed in theeye. The polymeric carrier can be a solid biodegradable polymericmaterial such as a PLA, a PLGA or a mixture thereof, or a viscous,polymeric biodegradable carrier such as a hyaluronic acid or ahyaluronate. The release modifier can be a long chain fatty alcohols.The long chain fatty alcohol must be incorporated into oursustained-release intraocular drug delivery system at a temperatureabove their melt temperature (or in a cosolvent solution with polymer)in order to fill voids in the solid (anhydrous) polymer matrix. Ahyaluronic acid-based polymers is not a preferred polymericbiodegradable carrier because hyaluronic acid-based polymers arehydrogels that degrade (depolymerize) upon heating. Preferably, thepolymeric carrier comprises a polymer selected from the group consistingof poly-lactic acid (PLA), poly-glycolic acid (PGA),poly-lactide-co-glycolide (PLGA), polyesters, poly (ortho ester),poly(phosphazine), poly (phosphate ester), polycaprolactones, gelatin,collagen, derivatives thereof, and combinations thereof.

A method of making the present systems involves combining or mixing thetherapeutic agent with the polymeric carrier to form a mixture. Themixture may then be extruded or compressed to form a single composition.The single composition may then be processed to form individual implantsor microparticles suitable for placement in an eye of a patient. Solidimplants suitable for use in our invention can be formed frompolymer-drug blends by such methods as thermal extrusion, solventcasting, or direct compression. Our invention requires a molecularmixture of polymer and a release modifier such as fatty alcohol. Hence acompression method for making an implant is useful only if heat isapplied to melt the polymeric matrix.

The implants can be placed in an ocular region to treat a variety ofocular conditions. Placement of the implants may be through surgicalimplantation, or through the use of an implant delivery device whichadministers the implant via a needle or catheter. The implants caneffectively treat conditions associated with neovascularization of theeye, such as the retina. The therapeutic agent can be released atcontrolled or predetermined rates when the implant is placed in the eye.Such rates may range from about 0.003 micrograms/day to about 5000micrograms/day.

Our invention encompasses a sustained release drug delivery system whichcomprises a water soluble therapeutic agent, a polymeric carrier for thetherapeutic agent, and a release modifier for modifying a release rateof the therapeutic agent from the polymeric carrier. The releasemodifier is an aliphatic alcohol. This sustained release drug deliverysystem can release a therapeutic amount of the therapeutic agent over aperiod of time of at least about one week.

The water soluble therapeutic agent in our sustained release drugdelivery system can be a protein or a polynucleotide, and the polymericcarrier can be a biodegradable polymer. Thus, the polymeric carrier canbe a poly-lactide-co-glycolide (PLGA) polymer. Preferably, the aliphaticalcohol release modifier is long chain fatty alcohol, that is a longchain fatty alcohol which comprises from 10 to 40 carbon atoms.

Our sustained release drug delivery system exhibits a substantiallylinear rate of release of the therapeutic agent in vivo over a period ofabout 50 days. By substantially linear rate of release it is meant thatthe therapeutic agent is released from the polymeric carrier under doesnot vary by more than about 100% over the desired period of time, moreusually by not more than about 50%.

The sustained release drug delivery system can release less that about30% of the therapeutic agent after about 5 days in vivo and less thatabout 80% of the therapeutic agent after about 50 days in vivo.

A preferred embodiment of our sustained release drug delivery system cancomprise (a) a water soluble therapeutic agent, wherein the watersoluble therapeutic agent is a protein or a polynucleotide; (b) abiodegradable polymeric carrier associated with the therapeutic agent,and; (c) a release modifier, wherein the release modifier has theformula R—(CH₂)_(n)—OH, where n is an integer between 8 and 40 and R isselected from the group consisting of CH₃—, a cyclic compound (such as afour or five carbon cyclic compound), a polycyclic compound and anaromatic (such as a benzyl group) compound, wherein the sustainedrelease drug delivery system can release a therapeutic amount of thetherapeutic agent over a period of time of at least about one week.

The release modifier can be capryl alcohol, pelargonic alcohol, capricalcohol, lauryl alcohol, myristyl alcohol, cetyl alcohol, palmitoleylalcohol, stearyl alcohol, isostearyl alcohol, elaidyl alcohol, oleylalcohol, linoleyl alcohol, polyunsaturated elaidolinoleyl alcohol,polyunsaturated linolenyl alcohol, elaidolinolenyl alcohol,polyunsaturated ricinoleyl alcohol, arachidyl alcohol, behenyl alcohol,erucyl alcohol, lignoceryl alcohol, ceryl alcohol, montanyl alcohol,cluytyl alcohol, myricyl alcohol, melissyl alcohol, and/or geddylalcohol.

Significantly, the sustained release drug delivery system can comprise apolymeric carrier which is a viscous aqueous carrier as opposed to asolid polymeric carrier. If a solid polymeric carrier it can be apoly-lactic acid (PLA), poly-glycolic acid (PGA),poly-lactide-co-glycolide (PLGA), polyesters, poly (ortho ester),poly(phosphazine), poly (phosphate ester), polycaprolactones, gelatin,collagen, derivatives thereof, and combinations thereof.

Our invention also includes a method for treating an ocular condition byintraocular placement of a sustained release drug delivery systemcomprising: (a) a water soluble therapeutic agent; (b) a polymericcarrier for the therapeutic agent, and; (c) a release modifier formodifying a release rate of the therapeutic agent from the polymericcarrier, wherein the release modifier is an aliphatic alcohol, and thesustained release drug delivery system can release a therapeutic amountof the therapeutic agent over a period of time of at least about oneweek. The step of intraocular placement is carrier out using anintraocular injector, such as using any of the injectors disclosed inU.S. Pat. Nos. 6,899,717; 7,090,681 or in U.S. patent application Ser.Nos. 10/917,909, 11/021,947.

The ocular condition can be, for example, uveitis, macular edema,macular degeneration, proliferative retinopathy, diabetic retinopathy,retinitis pigmentosa and/or glaucoma.

DRAWING

FIG. 1 is a graph cumulative % in vitro release of the polynucleotide23-mer ONT from a PLGA sustained release drug delivery system (“DDS”)upon formulation of the DDS with one of three different releasemodifiers (1-eicosanol, cholesterol, and PEG 3350) as compared tocumulative % in vitro release of the polynucleotide 23-mer ONT from thesame DDS formulated without a release modifier.

DESCRIPTION

We have discovered that sustained release of a water soluble therapeuticagent from a drug delivery device can be achieved by formulating thewater soluble drug with a polymeric carrier and certain releasemodifiers. The release modifier is preferably an aliphatic (i.e. longchain) fatty alcohol.

Injectable or implantable sustained release dosage forms containing awater soluble drug substances typically exhibit a large initial burstrelease of the drug followed by very low drug release levels. Thepresent invention encompasses use of long-chain fatty alcohols to modifythe release profile of water soluble drugs from injectable andimplantable sustained release systems. These release modifiers have noor a very low cytotoxicity.

The drug delivery system can be formulated as a solid polymeric implantor as a viscous injectable solution or dispersion. A formulation withinthe scope of our invention can comprise a drug, a polymeric carrier forthe drug and a long-chain fatty alcohol release modifier. The drugdelivery system can also comprise one or more additional drugs, polymerblends, fatty alcohol blends and excipients.

The fatty alcohols can have any chain length greater than about 6 carbonatoms, be straight chain or branched, saturated or unsaturated. We havefound that saturated straight chain alcohols comprising 16 to 26 carbonsare especially useful.

The drug delivery system can be in the form of a rod, tablet, capsule,sphere, microsphere, particle, sheet, filament, plaque or the like. Thedrug delivery system be present in a fluid vehicle for injection.Additionally, drug delivery system can be made by heat extrusion, coldpress, solvent casting, melt casting, solvent evaporation and otherknown procedures.

A preferred release modifier is a biocompatible long chain fattyalcohol, such as 1-eicosanol, which is shown below:

More preferred long-chain fatty alcohols are not branched and have from16-26 carbons.

Cholesterol (C27H45OH), and

PEG-3350 [HO(C₂H₄O)_(n), a synthetic polyglycol having an averagemolecular weight of 3350], can both be considered to be long chain fattyalcohols, but these two particular long chain fatty alcohols areexcluded from the scope of our invention because we determined throughexperiment that they are not suitable release modifier to use in thedrug delivery systems disclosed herein.

Without intending to be bound by theory we can hypothesize that a longchain fatty alcohol can have utility as a release modifier in the drugdelivery systems disclosed herein because these waxy molecules areparticularly effective at blocking many of the pores and voids that areknown to be present in a polymeric matrix. This blocking effect can berelated to the melting points of our preferred fatty alcohols which arenear or below the glass transition temperature for PLGA-type polymers,i.e., typically about 75-100° C. Melting points for the above listedfatty alcohols are as follows: 56° C. for C16; 57° C. for C18, 65° C.for C20, and 69° C. for C22. In effect, melted fatty alcohol may serveas “mortar” between the polymer “bricks”. In the case of highlywater-soluble compounds such as SIRNA-027, pores and voids allow waterto permeate the matrix, thereby rapidly dissolving the encapsulateddrug. While cholesterol is a fatty alcohol, the melt point is much toohigh (148° C.) to allow flow into these voids and pores. The long chainfatty alcohols useful as release modifiers in our invention are slowlyremoved from pores on the surface of our disclosed polymeric implantdrug delivery systems since they are at least poorly water-soluble, anddiffusion-limited drug release can continue as required.

Preferred release modifiers can be a long-chain fatty alcohols such as1-hexadecanol (cetyl alcohol; C16), 1-octadecanol (stearyl alcohol;C18), 1-eicosanol (arachidyl alcohol; C20), and 1-docosanol (behenylalcohol; C22). A fatty alcohol with an aliphatic chain shorter thanabout 14, for example 10 or less carbon atoms is sufficiently morewater-soluble, meaning that it will be removed too quickly from theadministered polymeric implant and is therefore not suitable for use inour drug delivery systems.

Controlled and sustained administration of one or more therapeuticagents through the use of our intraocular drug delivery systems, such asintraocular implants or polymeric particles, can effectively treat oneor more ocular conditions. The present drug delivery systems comprise apharmaceutically acceptable polymeric carrier and are formulated torelease one or more pharmaceutically active agents over an extendedperiod of time, such as for more than one week, and in certainembodiments for a period of time of one year or more. Thus, the presentdrug delivery systems can comprise a polymeric carrier for a watersoluble drug, the water soluble drug (therapeutic agent), and a releasemodifier. The polymeric carrier can comprise one or more biodegradablepolymers, one or more biodegradable copolymers, one or morenon-biodegradable polymers, and one or more non-biodegradablecopolymers, and combinations thereof. The polymeric carrier is a drugrelease sustaining component. The therapeutic agent of the present drugdelivery systems is a water soluble therapeutic agents. Examples ofwater soluble therapeutic agents include peptides, proteins, nucleicacids, antibodies, and antibody fragments. For example, the therapeuticagent of the present drug delivery systems can comprise, consistessentially of, or consist entirely of, one or more therapeutic agentsselected from the group consisting of anti-angiogenesis compounds,ocular hemorrhage treatment compounds, macromolecular non-steroidalanti-inflammatory agents, growth factor inhibitors (e.g. VEGFinhibitors), growth factors, cytokines, antibodies, oligonucleotideaptamers, antisense oligonucleotides small interfering ribonucleic acid(siRNA) molecules and antibiotics. The present drug delivery systems areeffective to provide a therapeutically effective dosage(s) of the agentor agents directly to a region of the eye to treat, prevent, and/orreduce one or more symptoms of one or more undesirable ocularconditions. Thus, with each administration therapeutic agents are madeavailable at the ocular site where they are needed and will bemaintained at effective concentrations for an extended period of time,rather than subjecting the patient to more frequent injections or, inthe case of self-administered drops, ineffective treatment with onlylimited bursts of exposure to the active agent or agents or, in the caseof systemic administration, higher systemic exposure and concomitantside effects or, in the case of non-sustained release dosages,potentially toxic transient high tissue concentrations associated withpulsed, non-sustained release dosing.

A controlled drug release is achieved by an improved formulation of slowrelease biodegradable implants. The release rate of a drug from animplant is modulated by addition of a release modulator to the implant.The release modulator is a long chain (8-40 carbon atoms) fatty alcoholwhich is physiologically inert.

The rate of release of the therapeutic agent can be controlled by therate of transport of the therapeutic agent through the polymeric matrixof the carrier, porosity of the polymeric matrix and the action of therelease modifier. By modulating the release rate, the therapeutic agentis released at a substantially constant rate, or within a therapeuticdosage range, over the desired period of time. The rate of release willusually not vary by more than about 100% over the desired period oftime, more usually by not more than about 50%. The therapeutic agent ismade available to the specific site(s) where the agent is needed, and itis maintained at an effective dosage. The transport of drug through thepolymer barrier can also be affected by drug solubility, polymerhydrophilicity, extent of polymer cross-linking, expansion of thepolymer upon water absorption so as to make the polymer barrier morepermeable to the drug, geometry of the implant, and the like.

The release modifier alters the release of a drug from a biodegradableimplant in a defined manner. The release modifier is a releaseretardant. Formulations of particular interest can have a therapeuticcombination of two or more active water soluble therapeutic agents,which provides for a sustained release of the agents.

In a preferred embodiment the present invention comprises an intraoculardrug delivery system comprising a therapeutic agent comprising ananti-angiogenic and/or a neuroprotectant polypeptide, a polymericcarrier and a long chain fatty alcohol as a release modifier. Even morepreferably, the present invention comprises at least a portion of anaturally occurring or synthetic antibody or antibody mimic having theability to inhibit human VEGF activity. In one specific embodiment thetherapeutic agent comprises a humanized anti-VEGF antibody, or fragmentthereof, including a Fab fragment.

In another preferred embodiment the present invention comprises anintraocular drug delivery system that results in the intraocularadministration of a therapeutic agent comprising an RNAi oligonucleotide(which may be double stranded) able to inhibit the translation of atleast one VEGF or VEGFR mRNA species. In a particularly preferredembodiment the RNAi molecule comprises an siRNA oligonucleotide. Inanother preferred embodiment the siRNA is able to silence the expressionof the VEGFR-2 receptor in a target cell. The antiVEGF-2 siRNA maycomprise, for example, the following nucleotide sequences and theircomplementary oligonucleotide sequences, preferably their exactcomplements.

Preferably, though not exclusively, the polymeric carrier comprises abiodegradable polymer. The polymeric carrier may be understood to be adrug release sustaining component. The polymeric carrier can be joinedto the therapeutic agent covalently, or the therapeutic agent may bedispersed within a matrix comprising the polymeric carrier

A sustained-release intraocular drug delivery system in accordance withthe present disclosure comprises a therapeutic agent, a polymericcarrier and a release modifier associated with the therapeutic agent topermit the therapeutic agent to be released into the interior of an eyeof an individual for at least about one week after the drug deliverysystem is placed in the eye. In certain embodiments disclosed herein,the therapeutic agent can be released for at least about ninety daysafter placement in an eye, and may even be released for at least aboutone year after placement in the eye. The present drug delivery systemscan provide targeted delivery of macromolecule therapeutic agents tointraocular tissues, such as the retina, while overcoming problemsassociated with conventional drug delivery methods, such as intraocularinjection of non-sustained release compositions.

DEFINITIONS

For the purposes of this description, we use the following terms asdefined in this section, unless the context of the word indicates adifferent meaning.

“About” means plus or minus ten percent of the number, range or item soqualified.

“Intraocular drug delivery system” means a device structured, sized, orotherwise configured to be placed in an eye. The present drug deliverysystems are generally biocompatible with physiological conditions of aneye and do not cause unacceptable or undesirable adverse side effects.The present drug delivery systems are placed in an eye withoutdisrupting vision. The present drug delivery systems can be in the formof a plurality of particles, such as microparticles, or may be in theform of implants, which are larger in size than the present particles.

“Therapeutic agent” means a protein or a polynucleotide useful fortreating an ocular condition.

“Associated with” means mixed with, dispersed within, coupled to,covering, or surrounding.

“Ocular region” or “ocular site” means any area of the eye, includingthe anterior and posterior segment of the eye, and which generallyincludes, but is not limited to, any functional (e.g., for vision) orstructural tissues found in the eyeball, or tissues or cellular layersthat partly or completely line the interior or exterior of the eyeball.Ocular regions include the anterior chamber, the posterior chamber, thevitreous cavity, the choroid, the suprachoroidal space, the subretinalspace, the conjunctiva, the subconjunctival space, the episcleral space,the intracorneal space, the epicorneal space, the sclera, the parsplana, surgically-induced avascular regions, the macula, and the retina.

“Ocular condition” means a disease, ailment or condition which affectsor involves the eye or one of the parts or regions of the eye. Broadlyspeaking the eye includes the eyeball and the tissues and fluids whichconstitute the eyeball, the periocular muscles (such as the oblique andrectus muscles) and the portion of the optic nerve which is within oradjacent to the eyeball.

An anterior ocular condition is a disease, ailment or condition whichaffects or which involves an anterior (i.e. front of the eye) ocularregion or site, such as a periocular muscle, an eye lid or an eye balltissue or fluid which is located anterior to the posterior wall of thelens capsule or ciliary muscles. Thus, an anterior ocular conditionprimarily affects or involves the conjunctiva, the cornea, the anteriorchamber, the iris, the posterior chamber (behind the iris but in frontof the posterior wall of the lens capsule), the lens or the lens capsuleand blood vessels and nerve which vascularize or innervate an anteriorocular region or site.

Thus, an anterior ocular condition can include a disease, ailment orcondition, such as for example, aphakia; pseudophakia; astigmatism;blepharospasm; cataract; conjunctival diseases; conjunctivitis; cornealdiseases; corneal ulcer; dry eye syndromes; eyelid diseases; lacrimalapparatus diseases; lacrimal duct obstruction; myopia; presbyopia; pupildisorders; refractive disorders and strabismus. Glaucoma can also beconsidered to be an anterior ocular condition because a clinical goal ofglaucoma treatment can be to reduce a hypertension of aqueous fluid inthe anterior chamber of the eye (i.e. reduce intraocular pressure).

A posterior ocular condition is a disease, ailment or condition whichprimarily affects or involves a posterior ocular region or site such aschoroid or sclera (in a position posterior to a plane through theposterior wall of the lens capsule), vitreous, vitreous chamber, retina,retinal pigmented epithelium, Bruch's membrane, optic nerve (i.e. theoptic disc), and blood vessels and nerves which vascularize or innervatea posterior ocular region or site.

Thus, a posterior ocular condition can include a disease, ailment orcondition, such as for example, acute macular neuroretinopathy; Behcet'sdisease; choroidal neovascularization; diabetic uveitis; histoplasmosis;infections, such as fungal or viral-caused infections; maculardegeneration, such as acute macular degeneration, non-exudative agerelated macular degeneration and exudative age related maculardegeneration; edema, such as macular edema, cystoid macular edema anddiabetic macular edema; multifocal choroiditis; ocular trauma whichaffects a posterior ocular site or location; ocular tumors; retinaldisorders, such as central retinal vein occlusion, diabetic retinopathy(including proliferative diabetic retinopathy), proliferativevitreoretinopathy (PVR), retinal arterial occlusive disease, retinaldetachment, uveitic retinal disease; sympathetic opthalmia; VogtKoyanagi-Harada (VKH) syndrome; uveal diffusion; a posterior ocularcondition caused by or influenced by an ocular laser treatment;posterior ocular conditions caused by or influenced by a photodynamictherapy, photocoagulation, radiation retinopathy, epiretinal membranedisorders, branch retinal vein occlusion, anterior ischemic opticneuropathy, non-retinopathy diabetic retinal dysfunction, retinitispigmentosa, and glaucoma. Glaucoma can be considered a posterior ocularcondition because the therapeutic goal is to prevent the loss of orreduce the occurrence of loss of vision due to damage to or loss ofretinal cells or optic nerve cells (i.e. neuroprotection).

“Biodegradable polymer” means to a polymer or polymers which degrade invivo, and wherein erosion of the polymer or polymers over time occursconcurrent with or subsequent to release of the therapeutic agent.Specifically, hydrogels such as methylcellulose which act to releasedrug through polymer swelling are specifically excluded from the term“biodegradable polymer”. The words “biodegradable” and “bioerodible” areequivalent and are used interchangeably herein. A biodegradable polymermay be a homopolymer, a copolymer, or a polymer comprising more than twodifferent polymeric units.

“Treat”, “treating”, or “treatment” means reduction or resolution orprevention of an ocular condition, ocular injury or damage, or topromote healing of injured or damaged ocular tissue.

“Therapeutically effective amount” means the level or amount of agentneeded to treat an ocular condition, or reduce or prevent ocular injuryor damage without causing significant negative or adverse side effectsto the eye or a region of the eye.

Intraocular drug delivery systems have been developed which can releasedrug loads over various time periods. These systems, which when placedinto an eye of an individual, such as the vitreous of an eye, providetherapeutic levels of a therapeutic agent for extended periods of time(e.g., for about one week or more). In certain embodiments, thetherapeutic agent is selected from the group consisting ofanti-angiogenesis compounds, particularly anti-VEGF recombinantantibodies and antibody fragments such as rambizumab and bevacizumab,ocular hemorrhage treatment compounds, non-steroidal anti-inflammatoryagents, growth factor (e.g. VEGF) inhibitors, growth factors, cytokines,antibodies, oligonucleotide aptamers, siRNA molecules and antibiotics.The disclosed systems are effective in treating ocular conditions, suchas posterior ocular conditions, such as glaucoma, retinalneurodegeneration, and neovascularization, and generally improving ormaintaining vision in an eye.

The polymeric carrier of the present systems can comprise abiodegradable polymer. In certain embodiments, the therapeutic agent isassociated with the polymeric carrier as a plurality of biodegradableparticles. Such particles are smaller than the implants disclosedherein, and may vary in shape. For example, certain embodiments of thepresent invention utilize substantially spherical particles. Otherembodiments may utilize randomly configured particles, such as particlesthat have one or more flat or planar surfaces. The drug delivery systemmay comprise a population of such particles with a predetermined sizedistribution. For example, a major portion of the population maycomprise particles having a desired diameter measurement.

In other embodiments, the therapeutic agent is associated with thepolymeric carrier as a biodegradable implant. In one embodiment of thepresent invention, an intraocular implant comprises a biodegradablepolymer matrix. The biodegradable polymer matrix is one type of a drugrelease-sustaining component. The biodegradable intraocular implantcomprises a therapeutic agent associated with the biodegradable polymermatrix. The matrix degrades at a rate effective to sustain release of anamount of the therapeutic agent for a time greater than about one weekfrom the time in which the implant is placed in ocular region or ocularsite, such as the vitreous of an eye.

In certain embodiments, the therapeutic agent of the present drugdelivery systems is selected from the group consisting of anti-bacterialagents, anti-angiogenic agents, anti-inflammatory agents,neuroprotectant agents, growth factor inhibitors, such as VEGFinhibitors, growth factors, cytokines, intraocular pressure reducingagents, ocular hemorrhage therapeutic agents, and the like. Thetherapeutic agent may be any anti-angiogenic macromolecule, any ocularhemorrhage treatment macromolecule, any non-steroidal anti-inflammatorymacromolecule, any VEGF inhibitory macromolecule, any peptide oroligonucleotides-containing growth factor, any cytokine, or any peptideor oligonucleotide antibiotic that can be identified and/or obtainedusing routine chemical screening and synthesis techniques. For example,the macromolecule therapeutic agent may comprise an agent or regionselected from the group consisting of peptides, proteins, antibodies,antibody fragments (such as, without limitation, Fab fragments), andnucleic acids. Some examples include hyaluronidase (ocular hemorrhagetreatment compound), ranibizumab (Lucentis®), pegaptanib (Macugen), andVEGF inhibitors) inhibiting fragments thereof, bevacizumab (Avastin®)and VEGF inhibiting fragments thereof, pegaptanib (Macugen®) and VEGFinhibiting fragments thereof, rapamycin, cyclosporine and RNAi genesilencing oligonucleotides, such as anti-VEGFR-2 inhibitory RNAi and theRNAi oligonucleotides described elsewhere in this specification.

In certain embodiments, the therapeutic agent of the present drugdelivery systems comprises a short or small interfering ribonucleic acid(siRNA) or an oligonucleotide aptamer. For example, and in somepreferred embodiments, the siRNA has a nucleotide sequence that iseffective in inhibiting cellular production of vascular endothelialgrowth factor (VEGF) or VEGF receptors.

One specific example of a useful siRNA is available from AcuityPharmaceuticals (Pennsylvania) or Avecia Biotechnology under the nameCand5. Cand5 is a therapeutic agent that essentially silences the genesthat produce VEGF. Thus, drug delivery systems including an siRNAselective for VEGF can prevent or reduce VEGF production in a patient inneed thereof.

As mentioned above, another example of a useful siRNA is available fromSirna Therapeutics (Colorado) under the name siRNA Z. siRNA Z is achemically modified short interfering RNA (siRNA) that targets vascularendothelial growth factor receptor-1 (VEGFR-1). Some additional examplesof nucleic acid molecules that modulate the synthesis, expression and/orstability of an mRNA encoding one or more receptors of vascularendothelial growth factor are disclosed in U.S. Pat. No. 6,818,447(Pavco).

Other embodiments of the present systems may comprise an antibodyselected from the group consisting of anti-VEGF antibodies, anti-VEGFreceptor antibodies, anti-integrin antibodies, therapeutically effectivefragments thereof, and combinations thereof.

Antibodies useful in the present systems include antibody fragments,such as Fab′, F(ab)2, Fabc, and Fv fragments. The antibody fragments mayeither be produced by the modification of whole antibodies or thosesynthesized de novo using recombinant DNA methodologies, and furtherinclude “humanized” antibodies made by now conventional techniques. Thepresent systems can also comprise rapamycin (sirolimus). Rapamycin is apeptide that functions as an antibiotic, an immunosuppressive agent, andan anti-angiogenic agent.

Our drug delivery systems may also include salts of the therapeuticagents when appropriate. Pharmaceutically acceptable acid addition saltsare those formed from acids which form non-toxic addition saltscontaining pharmaceutically acceptable anions, such as thehydrochloride, hydrobromide, hydroiodide, sulfate, or bisulfate,phosphate or acid phosphate, acetate, maleate, fumarate, oxalate,lactate, tartrate, citrate, gluconate, saccharate and p-toluenesulphonate salts.

The polymeric carrier of the present drug delivery systems can comprisea polymer selected from the group consisting of biodegradable polymers,non-biodegradable polymers, biodegradable copolymers, non-biodegradablecopolymers, and combinations thereof. In certain preferred embodiments,the polymer is selected from the group consisting of poly-lactic acid(PLA), poly-glycolic acid (PGA), poly-lactide-co-glycolide (PLGA),polyesters, poly (ortho ester), poly(phosphazine), poly (phosphateester), polycaprolactones, gelatin, collagen, derivatives thereof, andcombinations thereof.

The present drug delivery systems may be in the form of a solid element,a semisolid element, or a viscoelastic element, or combinations thereof.For example, the present systems may comprise one or more solid,semisolid, and/or viscoelastic implants or microparticles.

The therapeutic agent may be in a particulate or powder form andentrapped by a biodegradable polymer matrix. Usually, therapeutic agentparticles in intraocular implants will have an effective average sizeless than about 3000 nanometers. However, in other embodiments, theparticles may have an average maximum size greater than about 3000nanometers. In certain implants, the particles may have an effectiveaverage particle size about an order of magnitude smaller than 3000nanometers. For example, the particles may have an effective averageparticle size of less than about 500 nanometers. In additional implants,the particles may have an effective average particle size of less thanabout 400 nanometers, and in still further embodiments, a size less thanabout 200 nanometers. In addition, when such particles are combined witha polymeric carrier, the resulting polymeric intraocular particles maybe used to provide a desired therapeutic effect.

The therapeutic agent of the present systems is preferably from about 1%to 90% by weight of the drug delivery system. More preferably, thetherapeutic agent is from about 5% to about 15% by weight of the system.In a preferred embodiment, the therapeutic agent comprises about 10% byweight of the system. In another embodiment, the therapeutic agentcomprises about 20% by weight of the system.

The release modifier of the present systems is preferably from about 1%to 30% by weight of the drug delivery system. More preferably, therelease modifier is from about 3% to about 20% by weight of the system.In a preferred embodiment, the release modifier comprises from about 5%to about 15% by weight of the system. In a particularly preferredembodiment of the present invention the therapeutic agent comprisesabout from about 5% to about 10% by weight of the drug delivery system.

Suitable polymeric materials or compositions for use in the implantinclude those materials which are compatible, that is biocompatible,with the eye so as to cause no substantial interference with thefunctioning or physiology of the eye. Such materials preferably includepolymers that are at least partially and more preferably substantiallycompletely biodegradable or bioerodible.

In addition to the foregoing, examples of useful polymeric materialsinclude, without limitation, such materials derived from and/orincluding organic esters and organic ethers, which when degraded resultin physiologically acceptable degradation products, including themonomers. Also, polymeric materials derived from and/or including,anhydrides, amides, orthoesters and the like, by themselves or incombination with other monomers, may also find use. The polymericmaterials may be addition or condensation polymers, advantageouslycondensation polymers. The polymeric materials may be cross-linked ornon-cross-linked, for example not more than lightly cross-linked, suchas less than about 5%, or less than about 1% of the polymeric materialbeing cross-linked. For the most part, besides carbon and hydrogen, thepolymers will include at least one of oxygen and nitrogen,advantageously oxygen. The oxygen may be present as oxy, e.g. hydroxy orether, carbonyl, e.g. non-oxo-carbonyl, such as carboxylic acid ester,and the like. The nitrogen may be present as amide, cyano and amino. Thepolymers set forth in Heller, Biodegradable Polymers in Controlled DrugDelivery, In: CRC Critical Reviews in Therapeutic Drug Carrier Systems,Vol. 1, CRC Press, Boca Raton, Fla. 1987, pp 39-90, which describesencapsulation for controlled drug delivery, may find use in the presentimplants.

Of additional interest are polymers of hydroxyaliphatic carboxylicacids, either homopolymers or copolymers, and polysaccharides.Polyesters of interest include polymers of D-lactic acid, L-lactic acid,racemic lactic acid, glycolic acid, polycaprolactone, and combinationsthereof. Generally, by employing the L-lactate or D-lactate, a slowlyeroding polymer or polymeric material is achieved, while erosion issubstantially enhanced with the lactate racemate.

Among the useful polysaccharides are, without limitation, calciumalginate, and functionalized celluloses, particularlycarboxymethylcellulose esters characterized by being water insoluble, amolecular weight of about 5 kD to 500 kD, for example.

Other polymers of interest include, without limitation, polyesters,polyethers and combinations thereof which are biocompatible and may bebiodegradable and/or bioerodible.

Some preferred characteristics of the polymers or polymeric materialsfor use in the present invention may include biocompatibility,compatibility with the therapeutic agent, ease of use of the polymer inmaking the drug delivery systems of the present invention, a half-lifein the physiological environment of at least about 6 hours, preferablygreater than about one day, not significantly increasing the viscosityof the vitreous, and water insolubility.

Also important to controlling the biodegradation of the polymer andhence the extended release profile of the drug delivery systems is therelative average molecular weight of the polymeric carried employed inthe present systems. Different molecular weights of the same ordifferent polymeric compositions may be included in the systems tomodulate the release profile. In certain systems, the relative averagemolecular weight of the polymer will range from about 9 to about 64 kD,usually from about 10 to about 54 kD, and more usually from about 12 toabout 45 kD.

In some drug delivery systems, copolymers of glycolic acid and lacticacid are used, where the rate of biodegradation is controlled by theratio of glycolic acid to lactic acid. The most rapidly degradedcopolymer has roughly equal amounts of glycolic acid and lactic acid.Homopolymers, or copolymers having ratios other than equal, are moreresistant to degradation. The ratio of glycolic acid to lactic acid willalso affect the brittleness of the system, where a more flexible systemor implant is desirable for larger geometries. The % of polylactic acidin the polylactic acid polyglycolic acid (PLGA) copolymer can be 0-100%,preferably about 15-85%, more preferably about 35-65%. In some systems,a 50/50 PLGA copolymer is used.

The biodegradable polymer matrix of the present systems can comprise amixture of two or more biodegradable polymers. For example, the systemmay comprise a mixture of a first biodegradable polymer and a differentsecond biodegradable polymer. One or more of the biodegradable polymerscan have terminal acid groups.

Release of a drug from an erodible polymer is the consequence of severalmechanisms or combinations of mechanisms. Some of these mechanismsinclude desorption from the implants surface, dissolution, diffusionthrough porous channels of the hydrated polymer and erosion. Erosion canbe bulk or surface or a combination of both. It may be understood thatthe polymeric carrier of the present systems is associated with thetherapeutic agent so that the release of the therapeutic agent into theeye is by one or more of diffusion, erosion, dissolution, and osmosis.As discussed herein, the matrix of an intraocular drug delivery systemmay release drug at a rate effective to sustain release of an amount ofthe therapeutic agent for more than one week after implantation into aneye. In certain systems, therapeutic amounts of the therapeutic agentare released for more than about one month, and even for about twelvemonths or more. For example, the therapeutic agent can be released intothe eye for a time period from about ninety days to about one year afterthe system is placed in the interior of an eye.

The release of the therapeutic agent from the intraocular systemscomprising a biodegradable polymer matrix may include an initial burstof release followed by a gradual increase in the amount of thetherapeutic agent released, or the release may include an initial delayin release of the therapeutic agent followed by an increase in release.When the system is substantially completely degraded, the percent of thetherapeutic agent that has been released is about one hundred. Comparedto existing implants, the systems disclosed herein do not completelyrelease, or release about 100% of the therapeutic agent, until afterabout one week of being placed in an eye.

It may be desirable to provide a relatively constant rate of release ofthe therapeutic agent from the drug delivery system over the life of thesystem. For example, it may be desirable for the therapeutic agent to bereleased in amounts from about 0.01 μg to about 2 μg per day for thelife of the system. However, the release rate may change to eitherincrease or decrease depending on the formulation of the biodegradablepolymer matrix. In addition, the release profile of the therapeuticagent may include one or more linear portions and/or one or morenon-linear portions. Preferably, the release rate is greater than zeroonce the system has begun to degrade or erode.

As discussed in the examples herein, the present drug delivery systemscomprise a therapeutic agent, a polymeric carrier and a release modifierassociated to release an amount of the therapeutic agent that iseffective in providing a concentration of the therapeutic agent in thevitreous of the eye in a range from about 0.2 nM to about 5 μM. Inaddition or alternatively, the present systems can release atherapeutically effective amount of the macromolecule at a rate fromabout 0.003 μg/day to about 5000 μg/day. The desired release rate andtarget drug concentration can vary depending on the particulartherapeutic agent chosen for the drug delivery system, the ocularcondition being treated, and the patient's health. Optimization of thedesired target drug concentration and release rate can be determinedusing routine methods known to persons of ordinary skill in the art.

The drug delivery systems, such as the intraocular implants, can bemonolithic, i.e. having the active agent or agents homogenouslydistributed through the polymeric matrix, or encapsulated, where areservoir of active agent is encapsulated by the polymeric matrix. Dueto ease of manufacture, monolithic implants are usually preferred overencapsulated forms. However, the greater control afforded by theencapsulated, reservoir-type implant may be of benefit in somecircumstances, where the therapeutic level of the drug falls within anarrow window. In addition, the therapeutic agent, including thetherapeutic agent(s) described herein, can be distributed in anon-homogenous pattern in the matrix. For example, the drug deliverysystem may include a portion that has a greater concentration of thetherapeutic agent relative to a second portion of the system. Thepresent drug delivery systems can be in the form of solid implants,semisolid implants, and viscoelastic implants, as discussed herein.

The intraocular implants disclosed herein can have a size of betweenabout 5 μm and about 2 mm, or between about 10 μm and about 1 mm foradministration with a needle, greater than 1 mm, or greater than 2 mm,such as 3 mm or up to 10 mm, for administration by surgicalimplantation. The vitreous chamber in humans is able to accommodaterelatively large implants of varying geometries, having lengths of, forexample, 1 to 10 mm. The implant may be a cylindrical pellet (e.g., rod)with dimensions of about 2 mm×0.75 mm diameter. Or the implant may be acylindrical pellet with a length of about 7 mm to about 10 mm, and adiameter of about 0.75 mm to about 1.5 mm.

The implants can also be at least somewhat flexible so as to facilitateboth insertion of the implant in the eye, such as in the vitreous, andaccommodation of the implant.

The total weight of the implant is usually about 250-5000 μg, morepreferably about 500-1000 μg. For example, an implant may be about 500μg, or about 1000 μg. However, larger implants may also be formed andfurther processed before administration to an eye. In addition, largerimplants may be desirable where relatively greater amounts of atherapeutic agent are provided in the implant, as discussed in theexamples herein. For non-human individuals, the dimensions and totalweight of the implant(s) may be larger or smaller, depending on the typeof individual. For example, humans have a vitreous volume ofapproximately 3.8 ml, compared with approximately 30 ml for horses, andapproximately 60-100 ml for elephants. An implant sized for use in ahuman may be scaled up or down accordingly for other animals, forexample, about 8 times larger for an implant for a horse, or about, forexample, 26 times larger for an implant for an elephant.

Drug delivery systems can be prepared where the center may be of onematerial and the surface may have one or more layers of the same or adifferent composition, where the layers may be cross-linked, or of adifferent molecular weight, different density or porosity, or the like.For example, where it is desirable to quickly release an initial bolusof drug, the center may be a polylactate coated with apolylactate-polyglycolate copolymer, so as to enhance the rate ofinitial degradation. Alternatively, the center may be polyvinyl alcoholcoated with polylactate, so that upon degradation of the polylactateexterior the center would dissolve and be rapidly washed out of the eye.

The drug delivery systems can be of any geometry including fibers,sheets, films, microspheres, spheres, circular discs, plaques and thelike. The upper limit for the system size will be determined by factorssuch as toleration for the system, size limitations on insertion, easeof handling, etc. Where sheets or films are employed, the sheets orfilms will be in the range of at least about 0.5 mm×0.5 mm, usuallyabout 3-10 mm×5-10 mm with a thickness of about 0.1-1.0 mm for ease ofhandling. Where fibers are employed, the fiber diameter will generallybe in the range of about 0.05 to 3 mm and the fiber length willgenerally be in the range of about 0.5-10 mm. Spheres may be in therange of about 0.5 μm to 4 mm in diameter, with comparable volumes forother shaped particles.

The size and form of the system can also be used to control the rate ofrelease, period of treatment, and drug concentration at the site ofimplantation. For example, larger implants will deliver aproportionately larger dose, but depending on the surface to mass ratio,may have a slower release rate. The particular size and geometry of thesystem are chosen to suit the site of implantation.

The proportions of therapeutic agent, polymer, and the release modifiercan be empirically determined by formulating several implants, forexample, with varying proportions of such ingredients. A USP approvedmethod for dissolution or release test can be used to measure the rateof release (USP 23; NF 18 (1995) pp. 1790-1798). For example, using theinfinite sink method, a weighed sample of the implant is added to ameasured volume of a solution containing 0.9% NaCl in water, where thesolution volume will be such that the drug concentration is afterrelease is less than 5% of saturation. The mixture is maintained at 37°C. and stirred slowly to maintain the implants in suspension. Theappearance of the dissolved drug as a function of time may be followedby various methods known in the art, such as spectrophotometrically,HPLC, mass spectroscopy, etc. until the absorbance becomes constant oruntil greater than 90% of the drug has been released.

The amount of active agent or agents employed in the drug deliverysystem, individually or in combination, will vary widely depending onthe effective dosage required and the desired rate of release from thesystem. As indicated herein, the agent will be at least about 1, moreusually at least about 10 weight percent of the system, and usually notmore than about 80.

In addition to the therapeutic agent, the intraocular drug deliverysystems disclosed herein may include an excipient component, such aseffective amounts of buffering agents, and antioxidants to protect adrug (the therapeutic agent) from the effects of ionizing radiation (αor β) during sterilization. Suitable water soluble buffering agentsinclude, without limitation, alkali and alkaline earth carbonates,phosphates, bicarbonates, citrates, borates, acetates, succinates andthe like, such as sodium phosphate, citrate, borate, acetate,bicarbonate, carbonate and the like. These agents are advantageouslypresent in amounts sufficient to maintain a pH of the system of betweenabout 2 to about 9 and more preferably about 4 to about 8. As such thebuffering agent may be as much as about 5% by weight of the totalsystem. Suitable water soluble preservatives include sodium bisulfite,sodium bisulfate, sodium thiosulfate, ascorbate, benzalkonium chloride,chlorobutanol, thimerosal, phenylmercuric acetate, phenylmercuricborate, phenylmercuric nitrate, parabens, methylparaben, polyvinylalcohol, benzyl alcohol, phenylethanol and the like and mixturesthereof. These agents may be present in amounts of from 0.001 to about5% by weight and preferably 0.01 to about 2% by weight.

Release modifiers are disclosed in U.S. Pat. No. 5,869,079. The amountof release modulator employed will be dependent on the desired releaseprofile, the activity of the modulator, and on the release profile ofthe therapeutic agent in the absence of modulator. Electrolytes such assodium chloride and potassium chloride may also be included in thesystems. Where the buffering agent or enhancer is hydrophilic, it mayalso act as a release accelerator. Hydrophilic additives act to increasethe release rates through faster dissolution of the material surroundingthe drug particles, which increases the surface area of the drugexposed, thereby increasing the rate of drug bioerosion. Similarly, ahydrophobic buffering agent or enhancer dissolve more slowly, slowingthe exposure of drug particles, and thereby slowing the rate of drugbioerosion.

In one embodiment our intravitreal drug delivery system can comprise abiodegradable polymer, such as PLGA, and a VEGF/VEGFR (particularlyrambizumab or bevacizumab or VEGF-inhibiting derivatives or fragments ofeither of these). The system can be in the form of a biodegradableintravitreal implant, or a population of biodegradable polymericmicroparticles. The drug delivery system includes an amount of aVEGF/VEGFR inhibitor that when released from the system, the inhibitorcan provide a therapeutic effect. For example, the biodegradable implantcan comprise a peptide, a nucleic acid molecule, a protein, or otheragent that interferes with interactions between VEGF and VEGFR. Examplesof useful inhibitors are described above. These drug delivery systemsprovide prolonged delivery of the VEGF inhibitor directly into thevitreous of an eye in need of treatment. Thus, these drug deliverysystems can provide effective treatment of one or more ocularconditions, including without limitation, neovascularization, oculartumors, and the like.

Embodiments of the present invention also relate to compositionscomprising the present drug delivery systems. For example, and in oneembodiment, a composition may comprise the present drug delivery systemand an ophthalmically acceptable carrier component. Such a carriercomponent may be an aqueous composition, for example saline or aphosphate buffered liquid.

The present drug delivery systems are preferably administered topatients in a sterile form. For example, the present drug deliverysystems, or compositions containing such systems, may be sterile whenstored. Any routine suitable method of sterilization may be employed tosterilize the drug delivery systems. For example, the present systemsmay be sterilized using radiation. Preferably, the sterilization methoddoes not reduce the activity or biological or therapeutic activity ofthe therapeutic agents of the present systems. Sterilization by heat orgas (ethylene oxide) is not used for our drug delivery systems since theformer sterilization method can result in polymer degradation anddeformation and the latter sterilization method can result in formationor deposit of unacceptable chemical residues. The only practicalsterilization method for use for our drug delivery systems is by gammaor beta irradiation, with the beta irradiation being preferred due toless heat buildup.

Various techniques may be employed to produce the drug delivery systemsdescribed herein. Useful techniques include, but are not necessarilylimited to, solvent evaporation methods, phase separation methods,interfacial methods, molding methods, injection molding methods, thermalextrusion methods, co-extrusion methods, carver press method, diecutting methods, heat compression, combinations thereof and the like.

Specific methods are discussed in U.S. Pat. No. 4,997,652. Extrusionmethods may be used to avoid the need for solvents in manufacturing.When using extrusion methods, the polymer and drug are chosen so as tobe stable at the temperatures required for manufacturing, usually atleast about 85 degrees Celsius. Extrusion methods use temperatures ofabout 25 degrees C. to about 150 degrees C., more preferably about 65degrees C. to about 130 degrees C. An implant may be produced bybringing the temperature to about 60 degrees C. to about 150 degrees C.for drug/polymer mixing, such as about 130 degrees C., for a time periodof about 0 to 1 hour, 0 to 30 minutes, or 5-15 minutes. For example, atime period may be about 10 minutes, preferably about 0 to 5 min. Theimplants are then extruded at a temperature of about 60 degrees C. toabout 130 degrees C., such as about 75 degrees C. In addition, theimplant may be coextruded so that a coating is formed over a core regionduring the manufacture of the implant.

Compression methods may be used to make the drug delivery systems, andtypically yield elements with faster release rates than extrusionmethods. Compression methods may use pressures of about 50-150 psi, morepreferably about 70-80 psi, even more preferably about 76 psi, and usetemperatures of about 0 degrees C. to about 115 degrees C., morepreferably about 25 degrees C.

The present systems may be configured to release the therapeutic agentinto the eye at a rate from about 0.003 μg/day to about 5000 μg/day.Thus, the foregoing methods may combine the polymeric carrier and thetherapeutic agent to form a drug delivery system with such desirablerelease rates. In addition, the present systems can be configured toprovide amounts of the macromolecule therapeutic agent that are clearedfrom the vitreous at a desired target rate. As described in theexamples, the clearance rates can range from about 3 mL/day to about 15mL/day. However, certain implants can release therapeutically effectiveamounts of the macromolecule therapeutic agent that are cleared from thevitreous at lower rates, such as less than about 1 mL/day. For example,Gaudreault et al. (“Preclinical pharmacokinetics of ranibizumab(rhuFabV2) after a single intravitreal administration”, IOVS, (2005);46(2):726-733) reports that ranibizumab can be cleared from the vitreousat rates of about 0.5 to about 0.7 mL/day when a ranibuzmab formulationis intravitreally injected.

The present systems can be formed by extruding a polymericcarrier/therapeutic agent mixture without disrupting the biologicalactivity of the macromolecule therapeutic agent. For example, implantshave been invented which include a macromolecule that retains itsstructure after an extrusion process. Thus, in spite of themanufacturing conditions, drug delivery systems in accordance with thedisclosure herein have been invented which include biologically activemacromolecules.

The drug delivery systems of the present invention can be inserted intothe eye, for example the vitreous chamber of the eye, by a variety ofmethods, including intravitreal injection or surgical implantation. Forexample, the drug delivery systems may be placed in the eye usingforceps or a trocar after making a 2-3 mm incision in the sclera.Preferably, the present systems can be placed in an eye without makingan incision. For example, the present systems may be placed in an eye byinserting a trocar or other delivery device directly through the eyewithout an incision. The removal of the device after the placement ofthe system in the eye can result in a self-sealing opening. One exampleof a device that may be used to insert the implants into an eye isdisclosed in U.S. patent publication 2004/0054374. The method ofplacement may influence the therapeutic agent or drug release kinetics.For example, delivering the system with a trocar may result in placementof the system deeper within the vitreous than placement by forceps,which may result in the system being closer to the edge of the vitreous.The location of the system may influence the concentration gradients oftherapeutic agent or drug surrounding the element, and thus influencethe release rates (e.g., an element placed closer to the edge of thevitreous may result in a slower release rate).

Ocular conditions treatable using the drug delivery systems disclosedherein include: maculopathies/retinal degeneration: maculardegeneration, including age related macular degeneration (ARMD), such asnon-exudative age related macular degeneration and exudative age relatedmacular degeneration, choroidal neovascularization, retinopathy,including diabetic retinopathy, acute and chronic macularneuroretinopathy, central serous chorioretinopathy, and macular edema,including cystoid macular edema, and diabetic macular edema.Uveitis/retinitis/choroiditis: acute multifocal placoid pigmentepitheliopathy, Behcet's disease, birdshot retinochoroidopathy,infectious (syphilis, lyme, tuberculosis, toxoplasmosis), uveitis,including intermediate uveitis (pars planitis) and anterior uveitis,multifocal choroiditis, multiple evanescent white dot syndrome (MEWDS),ocular sarcoidosis, posterior scleritis, serpignous choroiditis,subretinal fibrosis, uveitis syndrome, and Vogt-Koyanagi-Haradasyndrome. Vascular diseases/exudative diseases: retinal arterialocclusive disease, central retinal vein occlusion, disseminatedintravascular coagulopathy, branch retinal vein occlusion, hypertensivefundus changes, ocular ischemic syndrome, retinal arterialmicroaneurysms, Coat's disease, parafoveal telangiectasis, hemi-retinalvein occlusion, papillophlebitis, central retinal artery occlusion,branch retinal artery occlusion, carotid artery disease (CAD), frostedbranch angitis, sickle cell retinopathy and other hemoglobinopathies,angioid streaks, familial exudative vitreoretinopathy, Eales disease.Traumatic/surgical: sympathetic ophthalmia, uveitic retinal disease,retinal detachment, trauma, laser, PDT, photocoagulation, hypoperfusionduring surgery, radiation retinopathy, bone marrow transplantretinopathy. Proliferative disorders: proliferative vitreal retinopathyand epiretinal membranes, proliferative diabetic retinopathy. Infectiousdisorders: ocular histoplasmosis, ocular toxocariasis, presumed ocularhistoplasmosis syndrome (PONS), endophthalmitis, toxoplasmosis, retinaldiseases associated with HIV infection, choroidal disease associatedwith HIV infection, uveitic disease associated with HIV Infection, viralretinitis, acute retinal necrosis, progressive outer retinal necrosis,fungal retinal diseases, ocular syphilis, ocular tuberculosis, diffuseunilateral subacute neuroretinitis, and myiasis. Genetic disorders:retinitis pigmentosa, systemic disorders with associated retinaldystrophies, congenital stationary night blindness, cone dystrophies,Stargardt's disease and fundus flavimaculatus, Bests disease, patterndystrophy of the retinal pigmented epithelium, X-linked retinoschisis,Sorsby's fundus dystrophy, benign concentric maculopathy, Bietti'scrystalline dystrophy, pseudoxanthoma elasticum. Retinal tears/holes:retinal detachment, macular hole, giant retinal tear. Tumors: retinaldisease associated with tumors, congenital hypertrophy of the RPE,posterior uveal melanoma, choroidal hemangioma, choroidal osteoma,choroidal metastasis, combined hamartoma of the retina and retinalpigmented epithelium, retinoblastoma, vasoproliferative tumors of theocular fundus, retinal astrocytoma, intraocular lymphoid tumors.Miscellaneous: punctate inner choroidopathy, acute posterior multifocalplacoid pigment epitheliopathy, myopic retinal degeneration, acuteretinal pigment epithelitis and the like.

In one embodiment, an implant is administered to a posterior segment ofan eye of a human or animal patient, and preferably, a living human oranimal. In at least one embodiment, an implant is administered withoutaccessing the subretinal space of the eye. However, in other embodimentsthe implant may be inserted into the subretinal space. For example, amethod of treating a patient may include placing the implant directlyinto the posterior chamber of the eye. In other embodiments, a method oftreating a patient may comprise administering an implant to the patientby at least one of intravitreal placement, subretinal placement,subconjuctival placement, sub-tenon placement, retrobulbar placement,and suprachoroidal placement. Placement methods may include injectionand/or surgical insertion.

In at least one embodiment, a method of reducing neovascularization orangiogenesis in a patient comprises administering one or more implantscontaining one or more therapeutic agents, as disclosed herein to apatient by at least one of intravitreal injection, subconjuctivalinjection, sub-tenon injection, retrobulbar injection, andsuprachoroidal injection. A syringe apparatus including an appropriatelysized needle, for example, a 22 gauge needle, a 27 gauge needle or a 30gauge needle, can be effectively used to inject the composition with theposterior segment of an eye of a human or animal. Repeat injections areoften not necessary due to the extended release of the therapeutic agentfrom the implants.

EXAMPLES

The following examples illustrate aspect and embodiments of the presentinvention and are not intended to limit the scope of our invention.

Example 1 Manufacture and Testing of a Sustained Release Drug DeliverySystem with a Release Modifier

Biodegradable implants are made by combining about 10-20% by weight of atherapeutic agent, such as those agents described above, about with70-85% by weight of a biodegradable polymeric carrier, and about 5-10%by weight of a long chain fatty alcohol release modifier in a stainlesssteel mortar. The release modifier can be an aliphatic alcohol such ascapryl alcohol, pelargonic alcohol, capric alcohol, lauryl alcohol,myristyl alcohol, cetyl alcohol, palmitoleyl alcohol, stearyl alcohol,isostearyl alcohol, elaidyl alcohol, oleyl alcohol, linoleyl alcohol,polyunsaturated elaidolinoleyl alcohol, polyunsaturated linolenylalcohol, polyunsaturated elaidolinolenyl alcohol, polyunsaturatedricinoleyl alcohol, arachidyl alcohol, erucyl alcohol, lignocerylalcohol, ceryl alcohol, montanyl alcohol, cluytyl alcohol, myricylalcohol, melissyl alcohol and geddyl alcohol. The combination is mixedvia a Turbula shaker set at 96 RPM for 15 minutes. The powder blend isscraped off the wall of the mortar and then remixed for an additional 15minutes. The mixed powder blend is heated to a semi-molten state atspecified temperature for a total of 30 minutes, forming a polymer/drugmelt.

Rods are manufactured by pelletizing the polymer/drug melt using a 9gauge polytetrafluoroethylene (PTFE) tubing, loading the pellet into thebarrel and extruding the material at the specified core extrusiontemperature into filaments. The filaments are then cut into about 1 mgsize implants or drug delivery systems. The rods have dimensions ofabout 2 mm long×0.72 mm diameter. The rod implants weigh between about900 μg and 1100 μg.

Wafers are formed by flattening the polymer melt with a Carver press ata specified temperature and cutting the flattened material into wafers,each weighing about 1 mg. The wafers have a diameter of about 2.5 mm anda thickness of about 0.13 mm. The wafer implants weigh between about 900μg and 1100 μg.

In-vitro release testing can be performed on each lot of implant (rod orwafer). Each implant may be placed into a 24 mL screw cap vial with 10mL of Phosphate Buffered Saline solution at 37° C. and 1 mL aliquots areremoved and replaced with equal volume of fresh medium on day 1, 4, 7,14, 28, and every two weeks thereafter.

Drug assays may be performed by HPLC, which consists of a Waters 2690Separation Module (or 2696), and a Waters 2996 Photodiode ArrayDetector. An Ultrasphere, C-18 (2), 5 mm; 4.6×150 mm column heated at30° C. can be used for separation and the detector can be set at 264 nm.The mobile phase can be (10:90) MeOH-buffered mobile phase with a flowrate of 1 mL/min and a total run time of 12 min per sample. The bufferedmobile phase may comprise (68:0.75:0.25:31) 13 mM 1-Heptane SulfonicAcid, sodium salt—glacial acetic acid—triethylamine—Methanol. Therelease rates can be determined by calculating the amount of drug beingreleased in a given volume of medium over time in mg/day.

The polymers chosen for the implants can be obtained from BoehringerIngelheim or Purac America, for example. Examples of polymers include:RG502, RG752, R202H, R203 and R206, and Purac PDLG (50/50). RG502 is(50:50) poly(D,L-lactide-co-glycolide), RG752 is (75:25)poly(D,L-lactide-co-glycolide), R202H is 100% poly(D, L-lactide) withacid end group or terminal acid groups, R203 and R206 are both 100%poly(D, L-lactide). Purac PDLG (50/50) is (50:50)poly(D,L-lactide-co-glycolide). The inherent viscosity of RG502, RG752,R202H, R203, R206, and Purac PDLG are 0.2, 0.2, 0.2, 0.3, 1.0, and 0.2dL/g, respectively. The average molecular weight of RG502, RG752, R202H,R203, R206, and Purac PDLG are, 11700, 11200, 6500, 14000, 63300, and9700 daltons, respectively.

Example 2 Preparation and Therapeutic Use of an Anti-VEGF ExtendedRelease Implant(s)

VEGF (Vascular Endothelial Growth Factor) (also known as VEGF-A) is agrowth factor which can stimulate vascular endothelial cell growth,survival, and proliferation. VEGF is believed to play a central role inthe development of new blood vessels (angiogenesis) and the survival ofimmature blood vessels (vascular maintenance). Tumor expression of VEGFcan lead to the development and maintenance of a vascular network, whichpromotes tumor growth and metastasis. Thus, increased VEGF expressioncorrelates with poor prognosis in many tumor types. Inhibition of VEGFcan be an anticancer therapy used alone or to complement currenttherapeutic modalities (eg, radiation, chemotherapy, targeted biologictherapies).

An extended release bioerodible implant system can be used to treat anocular condition mediated by a VEGF. Thus, the implant can contain asactive agent a VEGF inhibitor. For example, either ranibizumab(Lucentis®; rhuFab V2) (or bevacizumab (Avastin®; rhuMab-VEGF), bothmade by Genentech, South San Francisco, Calif.), and the implant(s) anbe made using the method of Example 1. Ranibizumab and bevacizumab areboth anti-VEGF (vascular endothelial growth factor) antibody productsthat may have particular utility for patients with macular degeneration,including the wet form of age-related macular degeneration. The implantor implants can be loaded with a total of about 50 to about 500 μg ormore of the ranibizumab (i.e. about 150 μg of ranibizumab can be loadedinto the implants prepared according to the Example 1 method).Bevacizumab is approved as an antiangiogenic for the treatment ofcolorectal cancer at a concentration of 1 mg/ml. However, it iscurrently being divided by pharmacists into small portions(approximately 50 μl to approximately 100 μl in volume) for intravitrealinjection. The use of Avastin® for age-related macular degenerationwould benefit from inclusion into a extended release implant system inaccordance with the present invention. In addition, one or more implantdevice may be injected into the eye to deliver a higher amount of thedrug than would otherwise be given. Ranibizumab is a humanized Fab, anda derivative of the humanized anti-VEGF synthetic IgG1 bevacizumab. Itwill be understood that with regard to its inclusion into an implant ordrug delivery system according top the present invention, reference toranibizumab in the examples of this specification is substantiallyequally applicable to, and shall constitute a disclosure of the use inthe same manner of, bevacizumab.

The ranibizumab (or bevacizumab) extended release implant system orsystems can be implanted into an ocular region or site (i.e. into thevitreous) of a patient with an ocular condition for a desiredtherapeutic effect. The implant(s) can be inserted into the vitreoususing the procedure (trocar implantation) as described herein, or byincision. The implant(s) can release a therapeutic amount of theranibizumab for an extended period of time, such as for one 1 month, or2 months, or 3 months, or 4 months or 5 months or more, or even morethan six months, to thereby treat a symptom of the ocular condition.

An extended release bioerodible intraocular implant for treating anocular condition, such as an ocular tumor can also be made as set forthin Example 1, using about 1-3 mg of the VEGF Trap compound availablefrom Regeneron, Tarrytown, N.Y.

Example 3 Polymeric Drug Delivery Systems Containing siRNA Z

Drug delivery systems which comprise about 86.1 milligrams of siRNA Zcan be made using the process of Example 1. Such drug delivery systemscan release siRNA Z at a rate of from about 49.7 micrograms per day toabout 4970 micrograms per day. The release rates can be measured usingin vitro and/or in vivo assays as described above. Placement of thesiRNA Z drug delivery systems into the vitreous of an eye providetherapeutic benefits, such as the treatment of neovascularization andthe like, for at least about thirty days after a single administration.Improvements in patient function, such as vision and intraocularpressure, can be observed at longer time periods.

Example 4 Manufacture and Testing of Implants Containing SustainedRelease Drug Delivery System with Various Long Chain Fatty Alcohol aRelease Modifiers

We made and tested PLGA implant filaments designed for the sustainedrelease of a therapeutic agent, such as a therapeutic polynucleotide.Each implant made weighed about 400 mg. To made the implants,freeze-dried oligonucleotide (23-mer ONT; 40 mg or 10% w/w) was blendedseparately with the one of the excipient fatty alcohols used;cholesterol, polyethylene glycol 3350 (PEG-3350) or 1-eicosanol. Thefatty alcohol release modifier comprised 20 mg or 5% w/w of eachnon-control implant prepared. Powdered PLGA (Resomer RG-752, BoehringerIngelheim) made up the remaining 85% by weight of the 400 mg non-controlimplants made. The blended powder (polynucleotide, release modifier andpolymer resomer) was heated to about 77° C. and then processed into thinfilaments using a piston extruder fitted with a 500 μm exit nozzle.Filaments were cut into segments (about 6 mm long) and incubated intubes containing phosphate buffered saline (pH 7.4) using a shaker waterbath set at 37° C. At selected time intervals, release media was removedfor ONT analysis by reverse-phase HPLC and fresh release media wasadded.

All tested excipients (the release modifiers) used in this experimentwere waxy solids at room temperature. Control PLGA 400 mg filaments (90%w/w PLGA and 10% w/w the ONT; no release modifier present in thecontrols) exhibited unacceptably high burst release of ONT (over 40%after 24 hours). Cholesterol and the polyethylene glycol 3350 (PEG-3350)effectively blocked burst release, but subsequent release rates wereextremely low for about 30 days and would not result in a therapeuticlevel of ONT in the target tissue. As shown by FIG. 1, unexpectedly, thefilaments containing the 1-eicosanol release modifier showed a low burstrelease followed by an almost linear, diffusion-controlled releaselasting at least 50 days.

All references, articles, publications and patents and patentapplications cited herein are incorporated by reference in theirentireties.

While this invention has been described with respect to various specificexamples and embodiments, it is to be understood that the invention isnot limited thereto and that it can be variously practiced within thescope of the following claims.

1.-8. (canceled)
 9. A method for treating an ocular condition associatedwith neovascularization of the eye in a patient, the method comprisingadministering an extruded biodegradable intraocular implant to thepatient by intravitreal injection, wherein the extruded biodegradableintraocular implant consists of: a) about 70-85% by weight of abiodegradable polymeric carrier, wherein the biodegradable polymericcarrier is a poly-lactide-co-glycolide (PLGA); b) about 10-20% by weightof an anti-VEGF antibody; and c) about 5-10% by weight of a saturatedstraight chain alcohol 16 to 26 carbon atoms in length.
 10. The methodof claim 9, wherein the anti-VEGF antibody is bevacizumab.
 11. Themethod of claim 9, wherein the ocular condition is choroidalneovascularization.
 12. The method of claim 9, wherein the implant isadministered to the patient via a needle.
 13. The method of claim 9,wherein said saturated straight chain alcohol is 1-eicosonal.